Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 434-434 ◽  
Author(s):  
Sumanta K. Pal ◽  
Guru Sonpavde ◽  
Neeraj Agarwal ◽  
Nicholas J. Vogelzang ◽  
Sandy Srinivas ◽  
...  
Keyword(s):  
Practice Patterns ◽  
Clear Cell ◽  
Selective Pressure ◽  
Clinical Care ◽  
Circulating Tumor Dna ◽  
Mechanisms Of Resistance ◽  
First Line ◽  
Number Range ◽  
Entire Cohort ◽  
Tumor Dna

434 Background: Treatment of mRCC typically entails mechanistically distinct agents across the 1L and 2L setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. ctDNA is a platform to conveniently ascertain temporal changes in genomic profile. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 70 genes. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of 1L vs. 2L was performed, with grouping based on conventional practice patterns (1L regimens included sunitinib, pazopanib and bevacizumab, and 2L regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results: ctDNA results from 224 pts with mRCC were assessed (gender: 149 M, 75 F; average age: 62; histology: 89 clear cell, 37 non-clear cell, 98 unknown). GAs were detected in 78.6% of pts. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). 64 and 56 pts were coded as receiving 1L and 2L agents, respectively. The average number (range) of ctDNA alterations detected was 2.9 (1-14) in 1L and 3.7 (1-16) in 2L with median (range) ctDNA variant allele fractions of 0.23 (0.05-9.92) in 1L and 0.24 (0.04-47.14) in 2L. The highest disparity in GA frequencies in 2L vs. 1L were in TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%). Isolating 2L pts who specifically had 1L VEGF-therapy documented, these differences were even more prominent in comparison to 1L pts: TP53 (64% vs. 31%), PIK3CA (29% vs. 8%), and NF1 (29% vs. 4%). Conclusions: In the largest assessment of ctDNA in mRCC to date, the majority of pts demonstrated clinically relevant GAs. Increasing p53 and mTOR pathway (e.g, NF1, PIK3CA) alteration in 2L pts with 1L VEGF-directed therapy may underlie mechanisms of resistance. Increasing GA frequency from 1L to 2L pts may have implications for immunotherapeutic approaches.

Correlation between depression/anxiety and somatic circulating tumor DNA (ctDNA) alterations in patients with metastatic renal cell carcinoma (mRCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 649-649
Author(s):  
Cristiane Decat Bergerot ◽  
Paulo Gustavo Bergerot ◽  
Karen L. Clark ◽  
Matthew J. Loscalzo ◽  
Richard B. Lanman ◽  
...  
Keyword(s):  
Clear Cell ◽  
Clinical Care ◽  
Psychological Disorders ◽  
Psychosocial Interventions ◽  
Circulating Tumor Dna ◽  
Depression And Anxiety ◽  
Medication History ◽  
Genomic Alterations ◽  
Number Range ◽  
Entire Cohort

649 Background: A correlation between depression/anxiety and survival has been established in patients (pts) with mRCC (Cohen et al PLoS One 2012). We hypothesize that frequently encountered genomic alterations (GAs) in mRCC may identify pts with these psychological disorders. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 73 genes. Genomic alterations (GAs) were pooled for the entire cohort. ICD-9 diagnoses corresponding to anxiety and depression (300 and 311, respectively) were derived from detailed chart review, including review of established diagnoses and medication history. The chi-square test was used to determine the association between frequent GAs (those occurring in ≥5% of the study population) and the presence of depression and anxiety. Results: ctDNA results from 52 pts with mRCC were assessed (gender: 69.2% M, 30.8% F; average age: 58; histology: 84.6% clear cell, 15.4% non-clear cell). The most commonly used 1st-line treatment was sunitinib (46.1%). GAs were detected in 55.8% of pts. The most frequent GAs in the overall cohort included TP53 (21.1%), VHL (17.3%) and EGFR (7.7%). 5 and 8 pts were coded as having depression and anxiety, respectively. The average number (range) of ctDNA alterations detected was 1.1 (0-4) in patients with depression/anxiety and 1.6 (0-10) in those without (P = 0.001). The presence of VHL mutation was found to occur exclusively in pts with no depression/anxiety (P = 0.05), while 13 patients (25%) lacking VHL GAs had these psychological disorders. Conclusions: The absence of VHL alterations have been associated with poorer survival in pts with RCC (Patard et al Int J Cancer 2008), and our findings suggest that these patients may further have higher rates of depression/anxiety. Our data imply that patients bearing mutations in VHL may a prime target for early psychosocial interventions.

Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21207-e21207
Author(s):  
Zhehai Wang ◽  
Xiao Han ◽  
Jun Guo ◽  
Ming Jia ◽  
Changbin Zhu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Synergetic Effect ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Long Term Outcome ◽  
Significant Difference ◽  
Previously Treated ◽  
Tumor Dna

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

scholarly journals Comparative Analysis of Two Methods for the Detection of EGFR Mutations in Plasma Circulating Tumor DNA from Lung Adenocarcinoma Patients

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 803 ◽  
Author(s):  
Ming-Szu Hung ◽  
Jr-Hau Lung ◽  
Yu-Ching Lin ◽  
Yu-Hung Fang ◽  
Shu-Yi Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Egfr Mutation ◽  
Circulating Tumor Dna ◽  
Egfr Mutations ◽  
Cancer Tissue ◽  
Lung Cancer Tissue ◽  
First Line ◽  
Mutation Status ◽  
Egfr Tki ◽  
Tumor Dna

Mutations in the epidermal growth factor receptor (EGFR) are associated with various solid tumors. This study aimed to compare two methods for the detection of EGFR mutations in circulating tumor DNA (ctDNA) from lung adenocarcinoma (LUAD) patients and to evaluate the clinical significance of EGFR mutations in ctDNA. In this prospective cohort study, the EGFR mutation status of 77 patients with stage IIIB or IV LUAD was first determined using lung cancer tissue. The amplification refractory mutation system (ARMS) and single allele base extension reaction combined with mass spectroscopy (SABER/MassARRAY) methods were also used to detect EGFR mutations in plasma ctDNA from these patients and then compared using the EGFR mutation status in lung cancer tissue as a standard. Furthermore, the relationship between the presence of EGFR mutations in ctDNA after receiving first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and survival was evaluated. The overall sensitivity and specificity for the detection of EGFR mutations in plasma ctDNA by ARMS and SABER/MassARRAY were 49.1% vs. 56% and 90% vs. 95%, respectively. The agreement level between these methods was very high, with a kappa-value of 0.88 (95% CI 0.77–0.99). Moreover, 43 of the patients who carried EGFR mutations also received first-line EGFR-TKI therapy. Notably, patients with EGFR mutations in plasma ctDNA had significantly shorter progression-free survival (9.0 months, 95% CI 7.0–11.8, vs. 15.0 months, 95% CI 11.7–28.2; p = 0.02) and overall survival (30.6 months, 95% CI 12.4–37.2, vs. 55.6 months, 95% CI 25.8–61.8; p = 0.03) compared to those without detectable EGFR mutations. The detection of EGFR mutations in plasma ctDNA is a promising, minimally invasive, and reliable alternative to tumor biopsy, and the presence of EGFR mutations in plasma ctDNA after first-line EGFR-TKI therapy is associated with poor prognosis.

scholarly journals Favorable Outcomes in FGFR Fusion-Positive Cholangiocarcinomas and Evolution on Treatment Noted on Circulating Tumor DNA Liquid Biopsies

2020 ◽  
Vol 13 (2) ◽  
pp. 941-947
Author(s):  
Pashtoon Murtaza Kasi
Keyword(s):  
Selective Pressure ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Temporal Heterogeneity ◽  
Liquid Biopsies ◽  
Extrahepatic Cholangiocarcinoma ◽  
Molecular Aberrations ◽  
Provider Bias ◽  
Tumor Dna

Cholangiocarcinoma is a very heterogenous cancer and “target-rich” disease. While the current classifications are based on the anatomic location of these tumors (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), tumors within and across these disease groups have unique and often mutually exclusive molecular aberrations. Amongst these, fibroblast growth factor receptor 2 (FGFR2) fusion is one of the first amongst the list of “actionable” targets for which the US Food and Drug Administration just approved pemigatinib. This is for patients with cholangiocarcinoma who have received prior treatment and have FGFR2 fusion or another rearrangement. This was based on the results from the clinical trial FIGHT-202 (NCT02924376). At present, several FGFR inhibitors are actively being tested in several agnostic and tumor-specific clinical trials. Patients also have had the opportunity of getting access to some of these oral drugs through compassionate use programs. As a consequence, these patients have more options in addition to chemotherapy. These all tend to have “good” initial responses and improvement in performance status and later “acquired” mechanisms of resistance. The latter tend to often be gatekeeper mutations that bypass the inhibitory effects of these selective FGFR inhibitors and/or cause steric hindrance. These tumors, therefore, evolve on selective pressure (temporal heterogeneity). This can be captured noninvasively using “liquid biopsies” (circulating tumor DNA testing). Here we present cases (several years into treatment on average) showing the feasibility of using liquid biopsies (ctDNA testing) as well as the gain and later potential loss of intratumoral and temporal heterogeneity exhibited under selective pressure of these novel FGFR inhibitors, chemotherapy and/or locoregional therapies. Despite limitations in sample size and provider bias, it is important to identify these “exceptional responders” and/or better outcomes that may be inherent to the biology of FGFR fusion-positive cholangiocarcinomas.

Comparative circulating tumor DNA (ctDNA) genomic profiling in 110 patients with advanced renal cell carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 743-743
Author(s):  
Ritesh Kotecha ◽  
Erika Gedvilaite ◽  
Samuel J. Murray ◽  
Ashley Foster ◽  
Robert J. Motzer ◽  
...  
Keyword(s):  
Median Time ◽  
Cohort Analysis ◽  
Circulating Tumor Dna ◽  
Large Cohort ◽  
Comparative Approach ◽  
Detection Rates ◽  
Entire Cohort ◽  
Specific Tissue ◽  
Primary Tissue ◽  
Tumor Dna

743 Background: Circulating tumor DNA (ctDNA) profiling is a non-invasive method to genomically assess solid tumors. Key benchmarks are required to assess applications in RCC management. To evaluate this tool broadly, we performed a large cohort analysis using a comparative approach to correlate clinical characteristics and matched oncogenomics of primary tumor and ctDNA. Methods: Pts with prior NGS sequenced mutational profiles from tumor (nephrectomy or metastatic tissues) underwent a single-time point plasma collection for ctDNA extraction. ctDNA targeted NGS sequencing was performed using MSK-IMPACT, with bi-directional cross genotype comparison using Waltz 2.0. Liberal (1-2 reads) and stringent (≥3 reads) filters were applied, with a cut-off of <30% allele frequency to remove germline alterations. Relevant clinical parameters were analyzed for correlation with ctDNA alteration frequency and load. Results: 110 metastatic clear-cell RCC pts, of whom available IMDC-risk was favorable (25%), intermediate (45%), or poor (4%) were included. 96% of pts had a nephrectomy prior to ctDNA collection, and most were heavily pre-treated (mean: 3 therapies, R: 0-8). The median time from diagnosis to ctDNA collection was 22.1 months (R: 2.3-215), and the median time from site specific tissue sequencing was 23.8 months (R: 1-177). 587 alterations were identified across the entire cohort in primary tissues, and 65% of pts had ≥1 alteration in ctDNA by liberal criteria. Detection rates for VHL and PBRM1 alterations were different in primary tissue and ctDNA (both liberal and stringent) with VHL altered in 92%, 43% and 50%, respectively; and PBRM1 altered in 50%, 25%, 21%, respectively. Conclusions: This large cohort analysis shows comparable mutational profiles of RCC-specific alterations in primary tissue and ctDNA, and highlights challenges of liquid biopsy approaches in RCC. Future efforts to correlate clinical outcomes with algorithm-based metrics will enhance the utility of this tool.[Table: see text]

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